The advent of highly active anti-retroviral therapy (HAART) has permitted significant increases in survival and in quality of life in those HIV-infected individuals with access to advanced medical care and pharmaceuticals. With increased survival, and with effective prophylaxis and treatment for many previously lethal opportunistic infections, the manifestations of chronic diseases have become more prevalent in HIV-infected individuals. One such manifestation of chronic HIV infection is emphysema. Recent literature clearly documents the existence of accelerated emphysema, particularly in HIV-infected individuals who smoke cigarettes. The clinical literature has suggested that the CD8+ T cell may be important in the in the pathogenesis of HIV-related emphysema, but this relationship remains associational and speculative. Pneumocystis pneumonia remains an important cause of morbidity and mortality in HIV-infected individuals. Recently, the existence of carrier states for this infection have been identified, both in HIV-infected individuals and in those individuals who provide their care. Furthermore, Pneumocystis carriage is common in smokers with chronic obstructive pulmonary disease. Whether repeated bouts of Pneumocystis colonization or carriage contribute to lung damage, particularly in interaction with cigarette smoke, has not been investigated experimentally. Although HIV infection produces wide-ranging immunologic effects, depletion of CD4+ T cells remains the immunologic hallmark of HIV infection. Our laboratories have many years of experience studying the lungs of chronically CD4-depleted mice, as an immunologically valid animal model of HIV-induced immunosuppression. Furthermore, we have characterized the immunologic responses to chronic Pneumocystis infection in these CD4-depleted mice, a well-accepted animal model of this important opportunistic infection. In these investigations, the CD8+ T cell has emerged as an important mediator of lung inflammation and lung damage. Most recently, we have acquired expertise in the development and analysis of cigarette smoke-induced emphysema in mice. We hypothesize that, during persistent depletion of CD4+ T cells, chronic Pneumocystis colonization and cigarette smoke interact to cause emphysema. The development of emphysema is mediated by CD8+ T cells in the lung, and results from cytokine and perforin release. Furthermore, we hypothesize that CD8+ T cells drive the development of emphysema by damage to alveolar epithelial cells. RELEVANCE: Chronic manifestations of HIV infection, including emphysema, are likely to present increasing clinical challenges in the era of HAART, but the pathogenesis of HIV-related emphysema is not understood. Using immunologically relevant animal models, this project will investigate the pathogenesis of smoking-related emphysema during chronic immunosuppression, and will examine Pneumocystis as a relevant cofactor in the development of emphysema.